Neuropeptide Y (NPY), a 36 amino acid peptide, coexists with norepinephrine (NE) in most sympathetic postganglionic neurons; in fact, the sympathetic innervation of the cardiovascular system may invariably contain both NE and NPY. The aim of our studies is to establish the regulation of the release of NPY into the circulation, and actions of the peptide in the cardiovascular system. At the sympathetic neuroeffector junction, NPY cooperates with NE via at least three principally different mechanisms. First, like NE, NPY is a vasoconstrictor; however, not all vascular beds are responsive to NPY. Second, NPY suppresses stimulated NE release and reciprocally, NE appears to regulate NPY release. Third, MR and NE are post junctionally synergetic; hence, small amounts of NPY potentiates NE-evoked vasoconstriction while vessels preexposed to NE increase their responsiveness to NPY. Recently, we have provided evidence that in addition to the sympathoadrenomedullary system, platelets are a rich source of NPY which they release during secondary aggregation. Chromatographic (HPLC) characterization of platelet-derived NPY immunoreactivity revealed two major peaks: one co-eluted with authentic NPY, and the other one remains unidentified. The peak corresponding to authentic NPY increased 11-fold during platelet stimulation with collagen; the unidentified peak increased 4-fold. To elucidate a possible functional role of NPY on platelets, rat platelet membranes were assayed for 125I-NPY binding. High-density, saturable, high affinity binding sites for NPY were found on rat platelets. Analogous to some vessels, platelets were unresponsive to direct effects of NPY. However, effects of threshold or subthreshold concentrations of collagen were potentiated by NPY at concentrations as low as 10 M. Studies are under way to better characterize platelet and neuronal NPY systems (in rats and in humans), and their role in regulation of vascular and platelet functions.